N-Methyl-D-aspartate (NMDA) receptors play an important role in various central nervous system functions, such as synaptic transmission and synaptic plasticity, and underlying functions such as regulation of long-term potentiation, long-term depression, and experience, dependent synaptic refinement. Costa et al., “A Novel Family of Negative and Positive Allosteric Modulators of NMDA Receptors,” J. Pharmacol. Exp. Ther. 2010, 335, 614-621, at 614. Excitatory nerve transmission in these receptors is regulated by the neurotransmitter, L-glutamate, and the agonist, NMDA. PCT Intl. Publ. No. WO2007/006175, paras. 2-3. NMDA receptors are ligand-gated ion channels comprising seven subunits: GluN1, GluN2A-D, and GluN3A-B. Costa at 615. The NR2A and NR2B subunits have been implicated in glutamate binding to the receptor, while the NR1 subunit may play a role in the binding of the receptor co-agonist, glycine. The three-dimensional structures of the glutamate- and glycine-binding pockets of NMDA receptors have been characterized, allowing for design of more subtype-specific modulators.
Modulation of these receptors effects changes in learning and memory, and modulators of NMDA receptor activity are considered as potential treatments for neurological and psychiatric conditions including pain, neuropathic pain, inflammatory pain, peripheral neuropathy, stroke, epilepsy, neurodegeneration, schizophrenia, drug addiction, mood disorders, post-traumatic stress disorder, seizures, convulsions, age-associated memory impairment, and depression. Costa at 614. Modulation of NMDA receptor activity is linked with a neuroprotective role, with applications in treatments for stroke, traumatic brain injury, ischemia, and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. Costa at 614-615.
There is a particular need for NMDA receptor modulators that demonstrate subtype selectivity among members of the NMDA receptor family. Selective agents will allow for optimal therapeutic activity with a reduced potential for adverse side effects. Costa at 615.
There remains a need for potent NMDA receptor modulators with desirable pharmaceutical properties.